The effects of adolescent cannabinoid exposure on seizure susceptibility and lethality in adult male rats

Spring, Mitchell G.; Schoolcraft, Kathleen D.; López, Hassan H.

doi:10.1016/j.ntt.2015.12.005

Cited by 3 publications

(2 citation statements)

References 45 publications

(51 reference statements)

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“…Thus, we have preliminary evidence that the K1422E variant is associated with resistance to seizure generalization, but higher risk of death following a convulsive seizure. This further suggests that seizure generalization and lethality are separable phenotypes, which is the subject of a growing body of research 38,45,[47][48][49] .…”

Section: Discussionmentioning

confidence: 99%

Strain-dependent effects on neurobehavioral and seizure phenotypes inScn2a^K1422Emice

Echevarria-Cooper¹,

Hawkins²,

Kearney³

2023

Preprint

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Pathogenic variants inSCN2Aare associated with a range of neurodevelopmental disorders (NDD). Despite being largely monogenic,SCN2A-related NDD show considerable phenotypic variation and complex genotype-phenotype correlations. Genetic modifiers can contribute to variability in disease phenotypes associated with rare driver mutations. Accordingly, different genetic backgrounds across inbred rodent strains have been shown to influence disease-related phenotypes, including those associated with SCN2A-related NDD. Recently, we developed a mouse model of the variantSCN2A-p.K1422E that was maintained as an isogenic line on the C57BL/6J (B6) strain. Our initial characterization of NDD phenotypes in heterozygousScn2aK1422Emice revealed alterations in anxiety-related behavior and seizure susceptibility. To determine if background strain affects phenotype severity in theScn2aK1422Emouse model, phenotypes of mice on B6 and [DBA/2J x B6]F1 hybrid (F1D2) strains were compared. Convergent evidence from neurobehavioral assays demonstrated lower anxiety-like behavior inScn2aK1422Emice compared to wild-type and further suggested that this effect is more pronounced on the B6 background compared to the F1D2 background. Although there were no strain-dependent differences in occurrence of rare spontaneous seizures, response to the chemoconvulsant kainic acid revealed differences in seizure generalization and lethality risk, with variation based on strain and sex. Continued examination of strain-dependent effects in theScn2aK1422Emouse model could reveal genetic backgrounds with unique susceptibility profiles that would be relevant for future studies on specific traits and enable the identification of highly penetrant phenotypes and modifier genes that could provide clues about the primary pathogenic mechanism of the K1422E variant.

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Section: Discussionmentioning

confidence: 99%

Strain-dependent effects on neurobehavioral and seizure phenotypes inScn2a^K1422Emice

Echevarria-Cooper¹,

Hawkins²,

Kearney³

2023

Preprint

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“…Whereas chronic treatment with WIN results in slight CB 1 receptor desensitization in mice, it was much lower than when treated with Δ 9 -THC [65,66]. Similarly, evidence from rats with pentylenetetrazole (PTZ)-induced tonic-clonic seizures shows that chronic exposure to cannabinoids did not affect seizure susceptibility [67]. Therefore, the development of tolerance to CB 1 agonists seems to be dependent on several factors, including the used compound, experimental protocol, and dose [41,68].…”

Section: Discussionmentioning

confidence: 99%

Altered SWD stopping mechanism in WAG/Rij rats subchronically treated with the cannabinoid agonist R(+)WIN55,212-2

Perescis

Flipsen

Luijtelaar

et al. 2020

Epilepsy & Behavior

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A single injection of the cannabinoid agonist R(+)WIN55,212-2 (WIN) is known to cause an increase of the mean duration of spontaneously occurring spike-and-wave discharges (SWDs) in rats of the WAG/Rij strain, a genetic model for absence epilepsy. The aim of the present study was to establish whether repeated activation of CB 1 receptors with WIN leads to tolerance in its effect on SWD parameters, spectral density, and behavior over time. Adult male WAG/Rij rats (n = 16) were treated with WIN (6 mg/kg) or vehicle (olive oil). Injections (s.c.) took place 3 times per week during 2 weeks. Electroencephalogram (EEG) recordings, each lasting 24 h, were made 3 times: immediately before the first injection (baseline), immediately after the first injection (acute treatment), and after 2 weeks of treatment (subchronic treatment). The recordings were analyzed regarding incidence, durations of SWDs, and hazard rates of the durations of SWDs, the latter to describe SWD stopping probabilities. Putative changes in the spectral content of the EEG before and after WIN during active and passive behaviors were additionally investigated. Spike-and-wave discharge incidence was not affected by the acute and subchronic treatments. The mean duration of the SWDs was significantly longer than controls in the acute WIN-treated animals [11.9-s standard error of the mean (SEM): 0.64 compared with 8.4-s SEM: 0.25] as well as in subchronically treated animals (11.5-s SEM: 1.00 compared with 8.4-s SEM: 0.25). Hazard rates were significantly lower for WIN-treated animals at SWD durations in the 5.04-20.16-s range on both occasions. No effects of WIN on the frequency spectrum of the ongoing EEG were found, neither acutely nor after repeated administration. Evidence for tolerance was not found. The results on the mean duration and hazard rates suggest that stimulating the endocannabinoid system affects the SWD stopping mechanism, resulting in more long SWDs. We speculate that this effect is likely to be a direct result of CB 1 receptor agonism and a subsequent decrease in the availability of gamma-aminobutyric acid (GABA) in the reticular thalamic nucleus, which further weakens, in WAG/Rij rats already disturbed, the stopping mechanism of the SWDs.

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Disrupting the endocannabinoid system in early adolescence negatively impacts sociability

Cossio

Stadler

Michas

et al. 2020

Pharmacology Biochemistry and Behavior

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The effects of adolescent cannabinoid exposure on seizure susceptibility and lethality in adult male rats

Cited by 3 publications

References 45 publications

Strain-dependent effects on neurobehavioral and seizure phenotypes inScn2a^K1422Emice

Strain-dependent effects on neurobehavioral and seizure phenotypes inScn2a^K1422Emice

Altered SWD stopping mechanism in WAG/Rij rats subchronically treated with the cannabinoid agonist R(+)WIN55,212-2

Disrupting the endocannabinoid system in early adolescence negatively impacts sociability

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The effects of adolescent cannabinoid exposure on seizure susceptibility and lethality in adult male rats

Cited by 3 publications

References 45 publications

Strain-dependent effects on neurobehavioral and seizure phenotypes inScn2aK1422Emice

Strain-dependent effects on neurobehavioral and seizure phenotypes inScn2aK1422Emice

Altered SWD stopping mechanism in WAG/Rij rats subchronically treated with the cannabinoid agonist R(+)WIN55,212-2

Disrupting the endocannabinoid system in early adolescence negatively impacts sociability

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Strain-dependent effects on neurobehavioral and seizure phenotypes inScn2a^K1422Emice

Strain-dependent effects on neurobehavioral and seizure phenotypes inScn2a^K1422Emice